Activation of KCa3.1 by SKA‐31 induces arteriolar dilatation and lowers blood pressure in normo‐ and hypertensive connexin40‐deficient mice
Activation of KCa3.1 by SKA‐31 induces arteriolar dilatation and lowers blood pressure in normo‐ and hypertensive connexin40‐deficient mice
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SKAâ31 激活 KCa3 1 可诱导正常â和高血压连接蛋白40â缺陷小鼠的小动脉扩张并降低血压
DOI：
10.1111/bph.12267
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发表时间：
2013
影响因子：
7.3
通讯作者：
de Wit C
中科院分区：
文献类型：
--
作者：
Radtke J;Schmidt K;Wulff H;Köhler R;de Wit C
背景和目的钙激活钾通道KCa 3. 1在血管内皮中表达，其激活引起内皮超极化并启动内皮源性超极化（EDH）依赖性扩张。在这里，我们研究了KCa 3.1的药理学激活是否会扩张骨骼肌小动脉，以及连接蛋白40（Cx40）形成的肌内皮间隙连接是否是EDH型扩张和降压反应所必需的。实验方法我们在Cx40缺陷小鼠的提睾肌微循环和血压遥测中进行了活体显微镜检查。KCa3.1激活剂SKA-31诱导了明显的浓度依赖性小动脉EDH型扩张，达到最大扩张的约40%，并增强了ACh的作用。这些反应在缺乏KCa3.1通道的小鼠中不存在。相比之下，SKA-31诱导的炎症在具有Cx40缺陷的内皮细胞的小鼠中没有减弱（Cx40 fl/fl：Tie 2-Cre）。在分离的内皮细胞簇中，SKA-31在Cx40 fl/fl：Tie 2-Cre、普遍存在的Cx40缺陷小鼠（Cx40-/-）和对照组（Cx40 fl/fl）中诱导了相似幅度的超极化（约38 mV），这些超极化可被特异性KCa 3.1阻断剂TRAM-34逆转。在血压正常的野生型和Cx40 fl/fl：Tie 2-Cre以及高血压的Cx40-/-动物中，腹膜内注射SKA-31（30和100 mg·kg-1）使所有基因型的动脉压降低了32 mmHg。100 mg·kg-1 SKA-31的降压反应与心率降低有关。结论和意义我们得出结论，由药物激活KCa 3.1通道引起的内皮超极化诱导EDH型小动脉扩张，这与内皮Cx40和含Cx40的肌内皮缝隙连接无关。由于SKA-31降低了高血压Cx40缺陷小鼠的血压，KCa 3.1激活剂可能是治疗严重难治性高血压的有用药物。
Background and PurposeThe calcium‐activated potassium channel KCa3.1 is expressed in the vascular endothelium where its activation causes endothelial hyperpolarization and initiates endothelium‐derived hyperpolarization (EDH)‐dependent dilatation. Here, we investigated whether pharmacological activation of KCa3.1 dilates skeletal muscle arterioles and whether myoendothelial gap junctions formed by connexin40 (Cx40) are required for EDH‐type dilatations and pressure depressor responsesin vivo.Experimental ApproachWe performed intravital microscopy in the cremaster muscle microcirculation and blood pressure telemetry in Cx40‐deficient mice.Key ResultsIn wild‐type mice, the KCa3.1‐activator SKA‐31 induced pronounced concentration‐dependent arteriolar EDH‐type dilatations, amounting to ∼40% of maximal dilatation, and enhanced the effects of ACh. These responses were absent in mice devoid of KCa3.1 channels. In contrast, SKA‐31‐induced dilatations were not attenuated in mice with endothelial cells deficient in Cx40 (Cx40fl/fl:Tie2‐Cre). In isolated endothelial cell clusters, SKA‐31 induced hyperpolarizations of similar magnitudes (by ∼38 mV) in Cx40fl/fl:Tie2‐Cre, ubiquitous Cx40‐deficient mice (Cx40‐/‐) and controls (Cx40fl/fl), which were reversed by the specific KCa3.1‐blocker TRAM‐34. In normotensive wild‐type and Cx40fl/fl:Tie2‐Cre as well as in hypertensive Cx40‐/‐animals, i.p. injections of SKA‐31 (30 and 100 mg·kg−1) decreased arterial pressure by ∼32 mmHg in all genotypes. The depressor response to 100 mg·kg−1SKA‐31 was associated with a decrease in heart rate.Conclusions and ImplicationsWe conclude that endothelial hyperpolarization evoked by pharmacological activation of KCa3.1 channels induces EDH‐type arteriolar dilatations that are independent of endothelial Cx40 and Cx40‐containing myoendothelial gap junctions. As SKA‐31 reduced blood pressure in hypertensive Cx40‐deficient mice, KCa3.1 activators may be useful drugs for severe treatment‐resistant hypertension.
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影响因子：
20.1
作者：
Mather, S;Dora, KA;Garland, CJ
通讯作者：
Garland, CJ
影响因子：
4.8
作者：
Milkau, Malte;Kohler, Ralf;de Wit, Cor
通讯作者：
de Wit, Cor
大鼠中小和中级钙激活钾通道的开放引起松弛，主要由大动脉中一氧化氮的释放和小动脉中内皮衍生的超极化因子介导
影响因子：
3.5
作者：
E. Stankevičius;T. Dalsgaard;C. Krøigaard;Lilliana Beck;E. Boedtkjer;M. Misfeldt;Gorm Nielsen;Olav Schjorring;A. Hughes;U. Simonsen
通讯作者：
U. Simonsen
影响因子：
19.6
作者：
Schweda, Frank;Kurtz, Lisa;Wagner, Charlotte
通讯作者：
Wagner, Charlotte
DOI：
10.1073/pnas.97.14.8151
发表时间：
2000-07-05
影响因子：
11.1
作者：
Wulff, H;Miller, MJ;Chandy, KG
通讯作者：
Chandy, KG